Complex High-Content Phenotypic Screening

Horman, Shane R.

doi:10.5772/65387

Cited by 3 publications

(3 citation statements)

References 67 publications

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“…Studies have shown that findings from two-dimensional (2D, monolayer) cultured tumor cells differ from in vivo observations (Horman, 2016). Especially drug-induced regulation of HIF-1a observed in cell culture experiments has to be considered critical as solid tumors are often exposed to hypoxia and thus already feature HIF-1a overexpression (Zhong et al, 1999;Yang et al, 2017).…”

Section: Hif-1a Regulation By Opioids In Breast Cancer Cellsmentioning

confidence: 99%

Activation of HIF-1αbyδ-Opioid Receptors Induces COX-2 Expression in Breast Cancer Cells and Leads to Paracrine Activation of Vascular Endothelial Cells

Schoos

Gabriel

Knab

et al. 2019

J Pharmacol Exp Ther

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Opioids promote tumor angiogenesis in mammary malignancies, but the underlying signaling mechanism is largely unknown. The current study investigated the hypothesis that stimulation of d-opioid receptors (DOR) in breast cancer (BCa) cells activates the hypoxia-inducible factor 1a (HIF-1a), which triggers synthesis and release of diverse angiogenic factors. Immunoblotting revealed that incubation of human MCF-7 and T47D breast cancer cells with the DOR agonist D-Ala 2 ,D-Leu 5-enkephalin (DADLE) resulted in a transient accumulation and thus activation of HIF-1a. DADLE-induced HIF-1a activation preceded PI3K/Akt stimulation and was blocked by the DOR antagonist naltrindole and naloxone, pertussis toxin, different phosphoinositide 3-kinase (PI3K) inhibitors, and the Akt inhibitor Akti-1/2. Whereas DADLE exposure had no effect on the expression and secretion of vascular endothelial growth factor (VEGF) in BCa cells, an increased abundance of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE 2) was detected. DADLE-induced COX-2 expression was also observed in three-dimensional cultured MCF-7 cells and impaired by PI3K/Akt inhibitors and the HIF-1a inhibitor echinomycin. Supernatant from DADLEtreated MCF-7 cells triggered sprouting of endothelial (END) cells, which was blocked when MCF-7 cells were pretreated with echinomycin or the COX-2 inhibitor celecoxib. Also no sprouting was observed when END cells were exposed to the PGE 2 receptor antagonist PF-04418948. The findings together indicate that DOR stimulation in BCa cells leads to PI3K/Aktdependent HIF-1a activation and COX-2 expression, which trigger END cell sprouting by paracrine activation of PGE 2 receptors. These findings provide a potential mechanism of opioid-driven tumor angiogenesis and thus therapeutic targets to combat the tumor-angiogenic opioid effect. SIGNIFICANCE STATEMENT Opioids are indispensable analgesics for treating cancer-related pain. However, opioids were found to promote tumor growth and metastasis, which questions the use of these potent painrelieving drugs in cancer patients. Enhanced tumor vascularization after opioid treatment implies that tumor progression results from angiogenic opioid effects. Thus, understanding the signaling mechanism of opioid-driven tumor angiogenesis helps to identify therapeutic targets to combat these undesired tumor effects. The present study reveals that stimulation of d-opioid receptors in breast cancer cells leads to an activation of HIF-1a and expression of COX-2 via PI3K/Akt stimulation, which results in a paracrine activation of vascular endothelial cells by prostaglandin E 2 receptors.

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Section: Hif-1a Regulation By Opioids In Breast Cancer Cellsmentioning

confidence: 99%

Activation of HIF-1αbyδ-Opioid Receptors Induces COX-2 Expression in Breast Cancer Cells and Leads to Paracrine Activation of Vascular Endothelial Cells

Schoos

Gabriel

Knab

et al. 2019

J Pharmacol Exp Ther

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“…For drug discovery, two different complementary approaches can be applied: classical pharmacology , also known as phenotypic drug discovery , which is the historical basis of drug discovery, and reverse pharmacology or target-based drug discovery [ 13 ]. Target-based drug discovery is based on the formulation and testing of specific molecular hypotheses [ 13 ], while in phenotypic drug discovery, extracts or compounds are assessed against, for instance, cell lines in a quantitative measurement of one or more cellular parameters [ 14 ]. Both approaches differ in their first focus.…”

Section: Introductionmentioning

confidence: 99%

“…These two strategies have advantages and disadvantages and promote very different screening assays. Complex and advanced high-content phenotypic drug screenings have been developed in which 384- or 1536-well high-content screening plates are used to screen disease-relevant cell types assembled in a biomimetic fashion [ 14 ]. Organisms like fruit fly, zebrafish or mouse are commonly used for phenotypic screenings at the whole animal level [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Current Screening Methodologies in Drug Discovery for Selected Human Diseases

et al. 2018

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The increase of many deadly diseases like infections by multidrug-resistant bacteria implies re-inventing the wheel on drug discovery. A better comprehension of the metabolisms and regulation of diseases, the increase in knowledge based on the study of disease-born microorganisms’ genomes, the development of more representative disease models and improvement of techniques, technologies, and computation applied to biology are advances that will foster drug discovery in upcoming years. In this paper, several aspects of current methodologies for drug discovery of antibacterial and antifungals, anti-tropical diseases, antibiofilm and antiquorum sensing, anticancer and neuroprotectors are considered. For drug discovery, two different complementary approaches can be applied: classical pharmacology, also known as phenotypic drug discovery, which is the historical basis of drug discovery, and reverse pharmacology, also designated target-based drug discovery. Screening methods based on phenotypic drug discovery have been used to discover new natural products mainly from terrestrial origin. Examples of the discovery of marine natural products are provided. A section on future trends provides a comprehensive overview on recent advances that will foster the pharmaceutical industry.

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Multitargeting: An Alternative Approach to Tackle Multidrug Resistance in Tuberculosis

Patra

Hazra

Hazarika

2023

CDT

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Background: The prevalence of drug-resistant organisms has steadily increased over the past few decades worldwide. Especially in tuberculosis (TB) disease, the problems of co-morbidity and the rapid emergence of multidrug resistance have necessitated the development of multitarget-based therapeutic regimens. Several multitargeting compounds against Mycobacterium tuberculosis (Mtb) have been studied through novel in silico tools but these have rendered reduced efficacy in clinical trials. The authors have focussed on many exotic targets belonging to crucial Mtb survival pathways whose molecular structures and functions are underexplored. Likewise, insights into the hidden possibilities of promiscuous compounds from natural products or repurposed drugs to inhibit other cellular proteins apart from their validated targets are also depicted in this review. In addition to the existing line of drugs currently recommended for multidrug-resistant TB, newer host-directed therapies could also be fruitful. Furthermore, several challenges, including safety/efficacy ratios of multitarget compounds highlighted here, can also be circumnavigated by researchers to design “smart drugs” for improved tuberculosis therapeutics. Conclusion: A holistic approach towards alleviating the existing drawbacks of drug discovery in drug-resistant TB has been outlined. Finally, considering the current needs, the authors have put forward an overall summary of possible trends in multitargeting that are significant for futuristic therapeutic solutions.

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Complex High-Content Phenotypic Screening

Cited by 3 publications

References 67 publications

Activation of HIF-1αbyδ-Opioid Receptors Induces COX-2 Expression in Breast Cancer Cells and Leads to Paracrine Activation of Vascular Endothelial Cells

Activation of HIF-1αbyδ-Opioid Receptors Induces COX-2 Expression in Breast Cancer Cells and Leads to Paracrine Activation of Vascular Endothelial Cells

Current Screening Methodologies in Drug Discovery for Selected Human Diseases

Multitargeting: An Alternative Approach to Tackle Multidrug Resistance in Tuberculosis

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